Chronic pain is initiated in the periphery by either a nerve injury (“neuropathic pain”) or an inflammation. Both sources result in pain that is a major clinical problem that has mostly resisted effective treatment. Chronic pain can result from a number of causes, including trauma (accidental or surgical), metabolic conditions such as diabetes, and cancer.
Pain is the most common underlying symptom in cancer, occurring in about half of all patients with disease [11]. The absence of pain is associated with improved quality of life and perhaps survival [12]. Neuronal or neuropathic pain, which constitutes about half of all cancer pain, may be a result of tumor compression or tissue infiltration, as well as from direct neuronal involvement [13].
Chronic pain has a neurophysiologic correlate. Protein Kinase G-1α (PKG-1α) mediates the development of many types of chronic pain. PKG-1α is activated in axons at sites of injury or inflammation and subsequently transported retrogradely to the dorsal root ganglion (DRG) where it indirectly affects gene expression, leading to a long-term hyperexcitability (LTH) [10]. The DRG is part of the peripheral nervous system but communicates directly with the central nervous system. LTH enhances the activity of pain centers for extended periods of time, which is the root cause for chronic hyperalgesia (increased sensitivity to pain) and allodynia (pain from a stimulus that does not normally provoke pain). Significantly, activated PKG-1α is present only in the DRG whose nociceptive neurons are mediating chronic pain and is absent from motor axons.
Options for treating chronic pain are usually limited to the prescription of opioid analgesics that have untoward side effects such as sedation, addiction, and risk of overdose. In 2008, approximately 100 million U.S. adults were burdened by chronic pain [4] and most had been prescribed opioid pain relievers. In addition, an increasing number of patients simulate chronic pain symptoms in an effort to obtain the painkillers [5].
Prescription drug abuse is the fastest growing drug problem in the United States [1]. In 2008, more than 20,000 deaths occurred as a result of unintentional overdose of a prescription drug [2]. Nearly 15,000 of them were caused by prescription opioid analgesics, which is more than 3 times the 4,000 people killed by these drugs in 1999 [2]. In addition, for every overdose death, related to opioid analgesics, 10 persons were admitted for substance abuse treatment, 32 visited emergency departments due to prescription painkiller misuse or abuse, 130 reported drug dependence, and 825 reported nonmedical uses of opioid analgesics [3]. In 2010, one in 20 people in the United States, ages 12 and older, used prescription painkillers nonmedically [2]. Overall, nonmedical use of prescription pain relievers costs insurance companies up to $72.5 billion annually [2]. Thus, prescription analgesics misuse and abuse is an alarming and rapidly growing problem that that needs to be addressed on various levels.
The problems of misuse and abuse of prescription analgesics stem from the current lack of means of objective detection and assessment of chronic pain. With no objective evidence of chronic pain, physicians are left to rely mainly on patient testimony in identifying whether the pain originates from the peripheral or the central nervous system (and thus requires a certain treatment strategy), in matching the type of analgesic and its dose to the intensity of the pain, and in distinguishing actual chronic pain from simulation attempts. The alarming rate of prescription analgesics misuse and abuse combined with the growing utilization of opioid painkillers in clinical settings urgently call for development of a diagnostic tool for objective assessment of chronic pain.
A family of compounds that selectively bind to a chronic pain specific, activated form of protein kinase G-1α (PKG-1α) has been identified. This family, referred to as “NOP” compounds, is disclosed in United States Patent Application Publication No. 20080176920.